The present invention relates to a method for enhancing growth or improving feed efficiency in a human or non-human animal by reducing the binding between bacterial endotoxin and its cellular receptors in the gastrointestinal tract of the animal.
Enhancing animal growth or feed efficiency, can have substantial impact on, for example, the animal meat industry by reducing the high cost of feeding food-producing animals and directly improving profitability. For example, in the poultry industry, even a slight increase in broiler growth rate coupled with reduced feed consumption brings the broiler to market maturity faster at lower cost. With approximately eight billion broilers raised annually in the United States, significant savings are realized.
In animals, the gastrointestinal tract performs the function of digesting food and absorbing nutrients for the growth and other needs of the animals. The gastrointestinal tract is the primary residing place for the endogenous bacterial flora that include both gram-positive and gram-negative bacteria. Exogenous pathogenic bacteria also gain access to the gastrointestinal tract quite frequently. These bacteria can induce inflammatory responses in the gastrointestinal tract which increase tissue damage, cause the thickening of the gut wall, and negatively affect the ability of the animals, particularly mammals and avians, to efficiently digest food and absorb and use nutrients for growth.
Endotoxin, the bacterial lipopolysaccharide (LPS), is a characteristic outer membrane entity of gram-negative bacteria and a potent inducer of inflammatory responses. Although the exact mechanism on how endotoxin induces gastrointestinal inflammation is not clear, recent evidence suggests that endotoxin binds to receptors on host cells and the binding leads to the release of inflammatory mediators and activation of immune cells. Recent evidence further suggests that toll-like receptor 4 (TLR4) and CD14 act together as the cellular receptor for endotoxin to transduce signals. The association of MD2 to TLR4 may also be necessary in this regard. Endotoxin is shepherded to CD14 by LPS-binding protein (LBP). When bound by endotoxin, CD14 recruits and activates TLR4-MD2 complex to induce a cascade of downstream events that lead to inflammation responses. Since CD14 does not have a cytoplasmic domain, it relies on the cytoplasmic domain of TLR4 to transduce signals.
Reducing gastrointestinal inflammation can alter animal feeding behavior and improving animal health. Phospholipase A2 is an enzyme that is involved in the production of prostaglandins and leukotrienes, two important factors for causing gastrointestinal inflammation. U.S. Pat. Nos. 6,213,930 and 6,383,485 disclosed that feeding animals with anti-phospholipase A2 antibodies can reduce gastrointestinal inflammation, enhance animal growth and improve feed efficiency.
Although many studies have suggested that endotoxin from gram-negative bacteria induces inflammatory responses through binding to its cellular receptors, it is not clear whether reducing the binding in the gastrointestinal tract of an animal can reduce gastrointestinal inflammation, alter animal feeding behavior and improve animal health.